Dihydropyridine derivatives

0.4 Example 8 2.6

2.0 Example 9 2.9

5.6 Example 10 2.0

1.7 Example 11 8.0

2.9 Example 12 1.1

1.9 Example 13 14.2

4.2 control* 3.5

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*control: Nicardipine

The compound of the formula(I) of the present invention has a highly potential pharmacological action with marked long duration against cardiovascular diseases such as hypertension, angina pectoris, coronary artery thrombosis, myocardial infarction and cerebral blood flow disturbance. Accordingly, the compound of formula(I) of the invention are useful as remedies such as an anti-hypertensive agent, cerebral vasodilator, anti-stenocardiac agent, anti-cardiac infarction remedy and anti-arrhythmic agent, etc.

Accordingly, the present invention also provides a pharmaceutical composition which comprises the 1,4-dihydropyridine derivative of formula(I) as active ingredient with a pharmaceutically acceptable carrier, for preventing or treating the cardiovascular diseases. The compound of formula(I) of the invention is useful for preparing such a pharmaceutical composition not only due to its marked efficacy in curing and preventing hypertension, cerebral blood flow disturbance, stenocardiac. etc. but also due to its chemical stability, and resulting easiness of being prepared into various dosage forms. The compounds of formula(I) of the invention can be administered by oral, rectal and parenteral routes such as intravenous, subcutaneous and intramuscular administration.

When the compound of the formula(I) is used as the remedies the dose is different depending upon the administration route, the symptoms, age and sex of the patient. However, in the case of oral administration in normal adults, a daily administration of of 0.06-10 mg/kg/day once or over several doses is desirable, while for non-oral administration, the daily dose range is 0.006-1 mg/kg/day, also either given as a single dose or over several doses.

For oral administration forms such as tablets, pills, granules, powders, suspensions, capsules and the like can be used. They can be prepared by commonly known methods. In other words, tablets, pills, granules, powders, suspensions or capsules can be prepared by formulating appropriate combinations of compound(I) and excipients such as lactose, starch or the like, binders such as carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidine or the like, disintegrators such as crystalline cellulose, sodium alginate, sodium bicarbonate, sodium lauryl sulfate or the like, and lubricants such as talc, magnesium stearate, or the like.

Solutions and suspensions can be prepared by the ordinary skill in the art, using glycerol esters such as tricaprylin, triacetin, etc. and alcohols such as ethanol, etc.

The dosage forms for subcutaneous, intramuscular and intravenous administration are prepared in the form of an aqueous or non-aqueous solution.

In the preparation of an aqueous solutions, an isotonic sodium chloride solution or a buffer solution is used. In the preparation of non-aqueous solutions, propylene glycol, olive oil or ethyl oleate, etc., is used and, if required, antiseptics or stabilizers may be added.

Injections ca be sterilized by filtration through the membrane filter or by combination of disinfectants with other adjuvants.

The dosage forms for percutaneous administration are ointments and creams. Ointments can be prepared by commonly known methods using fatty oils such as castor oil, olive oil and vaseline, and creams are prepared by using fatty oils and emulsifying agents such as diethylene glycol, sorbitan monofatty acid ester, etc.

For rectal administration, ordinary suppositories in the form of soft gelatin capsules are used.

Other features of the invention will become apparent in the course of the following description of the exemplary embodiments which are given for illustration of the invention and are not intended to be limiting there of.

Preparation of 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methylthiomethyl ester 5-methyl ester

A solution of 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydro pyridine-3,5-dicarboxylic acid 5-methyl ester(3.32g), triethylamine(2.5ml)and chloromethyl methyl sulfide(0.9ml) in 30ml of acetonitrile was heated at 65° C. for 3 hours. The solvent was removed in vacuum, and then the residue was dissolved in ethylacetate. The ethylacetate solution was washed with water and dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The oily residue was purified by silica gel column chromatography (ethylacetate:n-hexane=1:3). The eluent was concentrated in vacuum to afford a yellow solid which was recrystallized from methyl alcohol to give the titled compound(1.2g):

m.p. 128°-130° C.,

1 H NMR(CDCl 3 ) ; 2.3(s, 3H), 2.4(s, 6H), 3.7(s, 2H), 6.4s, 1H), 7.1-8.6(m, 4H)

IR(KBr) cm -1 ; 3323(NH), 1701(C═O).

The following compounds were prepared by the similar method described in Example 1 and characterized in the form indicated, starting from the appropriate 1,4-dihydropyridine-3,5-dicarboxylate monoester.

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IR

Ex. No.

R.sup.1

R.sup.2

R.sup.3

Y m.p. (°C.)

H.sup.1 NMR(CDCl)

(KBr: cm.sup.-1)

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2. 3-nitro-

Me Et S 138-140

1.2(T, 3H), 2.0(s, 3H),

3326(NH)

phenyl 2.3(d, 6H), 4.1(q, 2H),

1696(C═O)

5.1(s, 1H+2H), 6.2(s, 1H),

7.6-8.2(m, 4H)

3. 3-nitro-

Me i-Pr

S 1.0-1.5(d, 6H), 2.1

3345(NH)

phenyl (s, 3H), 2.4(s, 6H),

1699(C═O)

5.1(m, 4H), 6.0(s, 1H),

1H), 7.2-8.3(m, 4H)

4. 3-nitro-

Et Me S 116- 1.2(t, 3H), 2.2-2.8

3341(NH),

phenyl 118(m, 8H), 3.7(s, 3H),

1704, 1654

5.2(s, 1H+2H), 6.5

(C═O)

5. 2,3- Me Me S 165-166

2.1(s, 3H), 2.3(d, 6H),

3337(NH),

dichloro- 3.6(s, 3H), 5.1(s 2H),

1701,

phenyl 5.5(s, 1H), 5.8(s, 1H),

1661(C═O)

6.9-7.5(m, 3H)

6. 2-tri-

Me Me S 104-107

2.1(s, 3H), 2.4(d, 6H),

3319(NH),

fluoro- 3.7(s, 3H), 4.9-5.1

1703,

methyl- (d+d, 2H), 5.6(s, 1H),

1677(C═O)

phenyl 5.9(s, 1H), 7.2-7.7

(m, 4H)

7. 3-nitro-

Me Me O 133-134

2.4(d, 6H), 3.4(s, 3H),

3340(NH),

phenyl 3.7(s, 3H), 5.2(m, 2H),

1707,

6.4(s, 1H), 7.2-8.2

1654(C═O)

(m, 4H)

8. 3-nitro

Me i-Pr

O 126-128

1.3(q, 6H), 2.4(d, 6H),

3340(NH),

phenyl 3.4(s, 3H), 5.2(m, 4H),

1651,

6.1(s, 1H), 7.2-8.2

1699(C═O)

(m, 4H)

9. 3-nitro-

Et Me O 115-116

1.2(t, 3H), 2.4(d, 6H),

3329(NH),

phenyl 3.5(q, 2H), 5.2(m, 2H),

1710(C═O)

6.2(s, 1H), 7.2-8.4

(m, 4H)

10. 2,3- Me Me O 130-131

2.3(d, 6H), 3.2(s, 3H),

3329(NH),

dichloro- 3.6(s, 3H), 5.0-5.5

1701,

phenyl (q, 2H), 5.5(s, 1H),

1666(C═O)

6.0(s, 1H), 6.9-7.5

11. 2,1,3-

Me Me S 121-123

2.0(s, 3H), 2.4(d, 6H),

3300(NH)

benzoxa- 3.6(s, 3H), 5.1(s, 2H),

1699,

diazole- 5.5(s, 1H), 6.5(s, 1H),

1646(C═O)

4-yl 7.2-7.7(m, 3H)

12. 2-nitro-

Me Me S 63-73 2.0(s, 3H), 2.3(d, 6H),

3484(NH),

phenyl 3.5(s, 3H), 5.0(dd, 2H),

1670(C═O)

5.6(s, 1H), 7.3-7.8

(m, 4H), 9.1(s, 1H)

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Preparation of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-phenylthiomethyl, 5-methylester

A solution of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 5-methyl ester (3.32 g), potassium carbonate(0.7 g), potassium iodide(1.7 g) and chloromethyl phenyl sulfide(1.34 ml) in 30 ml of dimethylformamide was stirred for 12 hours at room temperature. The reaction mixture was diluted with water and then extracted with dichloromethane. Organic layer was subsequently washed with brine, aqueous sodium hydroxide solution and water, and then dried over anhydrous sodium sulfate. The solvent was evaporated in vacuum. The residue was dissolved in ethyl alcohol to give 3.5 g. of yellow crystals:

m.p. 155°-157° C.,

1 H-NMR(CDCl 3 ) ; 2.4(s, 6H), 3.7(s, 3H), 5.1(s, 1H), 5.4(s, 2H), 6.2(s, 1H), 7.2-8.0(m, 9H)

IR(KBr) cm -1 ; 3337(NH), 1707(C═O).

Tablets were prepared using known procedures and the following ingredients. These tablets can be prepared into film coated or sugar coated tablets.

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Compound No. 1* 5.0 mg

Lactose 50.0 mg

Corn starch 25.0 mg

Crystalline Cellulose

25.0 mg

Methyl Cellulose 1.5 mg

Magnesium stearate 1.0 mg

Total 107.5 mg/tablet

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*Compound No. 1:

2,6dimethyl-4-(3nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid

3methylthiomethyl ester 5methyl ester

Granules were prepared using known procedures and the following ingredients, and then filled into No. 1 capsules.

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Compound No. 1 10 mg

Lactose 80 mg

Starch 30 mg

Talc 5 mg

Magnesium stearate 1 mg

Total 126 mg/capsule

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Injection was prepared according to known procedures and the following ingredients.

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Compound No. 1 4 g

Polyethylene glycol 4000

0.9 g

Sodium chloride 0.9 g

Polyoxyethylene sorbitan

0.4 g

monooleate

p-hydroxy methylbenzoate

0.18 g

p-hydroxy propylbenzoate

0.02 g

sterilized water 100 ml

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Obviously, numerous modification and variations of the present invention are possible in the light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.